The Role of Preoperative Chemotherapy in the Management of Synchronous Resectable Colorectal Liver Metastases: A Meta-Analysis

Background: The indications of preoperative chemotherapy, for initially resectable synchronous colorectal liver metastases, remain controversial. This meta-analysis aimed to assess the efficacy and safety of preoperative chemotherapy in such patients. Methods: Six retrospective studies were included in the meta-analysis with 1036 patients. Some 554 patients were allocated to the preoperative group, and 482 others were allocated to the surgery group. Results: Major hepatectomy was more common in the preoperative group than in the surgery group (43.1% vs. 28.8%, p < 0.001). Furthermore, the percentage of patients with more than three liver metastases was higher in the preoperative group compared to the surgery group (12.6% vs. 5.4%, p < 0.002). Preoperative chemotherapy showed no statistically significant impact on overall survival. Combined disease free/relapse survival analysis of patients with high disease burden (liver metastases > 3, maximum diameter > 5 cm, clinical risk score ≥ 3) demonstrated that there is a 12% lower risk of recurrence in favor of preoperative chemotherapy. Combined analysis showed a statistically significant (77% higher probability) of postoperative morbidity in patients who received preoperative chemotherapy (p = 0.002). Conclusions: Preoperative chemotherapy should be suggested in patients with high disease burden. The number of cycles of preoperative chemotherapy should be low (3–4) to avoid increased postoperative morbidity. However more prospective studies are needed to clarify the exact role of preoperative chemotherapy in patients with synchronous resectable colorectal liver metastases.


Introduction
Colorectal cancer (CRC) is a significant health burden representing 10% of all cancers. It is the third most commonly diagnosed cancer in males and the second in females, according to the World Health Organization GLOBOCAN database. CRC is the second cause of cancer-related mortality and accounts for 9.4% of worldwide cancer-related deaths [1].
It is estimated that 50-60% of patients diagnosed with CRC develop liver metastases during their disease course. Unfortunately, 80-90% of these patients are not suitable for potentially curative resection. Synchronous colorectal liver metastases (SCRLM) develop in 20-34% of patients with CRC [2][3][4][5]. Autopsy reports have demonstrated that more than

Materials and Methods
This systematic review and meta-analysis were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (PROSPERO id 411865) [22].

Literature Search
PubMed and Embase were searched from 1 January 2000 until 30 June 2021. The keywords: preoperative chemotherapy, neoadjuvant chemotherapy, synchronous colorectal liver metastases, resectable colorectal liver metastases and stage IV colorectal cancer were selected to identify all reports possibly related to the role of preoperative chemotherapy in the management of synchronous resectable colorectal liver metastases. Reference lists of all relevant studies and reviews were scanned further for additional studies. Study authors were contacted for unpublished studies or additional data.

Eligibility Criteria
Studies examining patients with synchronous resectable colorectal liver metastases aged 18 years or older were eligible. Different definitions of synchronous metastases can be found in the literature, and the adoption of a standardized definition is needed to clarify future reporting. In the present study, liver metastases were considered synchronous if detected on radiographic imaging in the perioperative period, intraoperatively during primary tumor resection or in the first 3 postoperative months. High disease burden was defined as patients with a Clinical Risk Score ≥3 [19], with a maximum diameter > 5 cm [16] or patients with more than three metastases [20].
All study designs, i.e., randomized control trials, cohort studies, case-control studies and case series examining the efficacy of preoperative chemotherapy in the management of synchronous resectable colorectal liver metastases, were included. Abstracts or conference communications not published as full articles in peer-reviewed journals were excluded. Additionally, review articles, case reports and editorials were ruled out. Restrictions were imposed on the publication date and language.
The patients were classified into two groups: those who received preoperative chemotherapy prior to liver resection and those who underwent upfront liver resection.

Outcomes
The primary outcomes were survival (OS) and disease-free survival (DFS). A subgroup analysis of patients with a high disease burden was also performed. Secondary outcomes encompassed R0 resection and morbidity.

Study Selection
After pilot testing eligibility criteria for citations and full-text articles, two reviewers screened the search results independently to select potentially eligible records based on title and abstract. Subsequently, the two reviewers confirmed the eligibility criteria independently based on the full-text articles of the relevant selected papers. Disputes were settled by discussion. If no agreement could be reached, a third reviewer would decide.

Data Collection and Extraction
The exact process was followed for data extraction. If needed, authors were contacted for studies including unclear or missing data. The two reviewers extracted information regarding characteristics of the study population (sex, mean age), primary tumor location (colon or rectal cancer), primary tumor size (T stage), lymph node status (N stage), liver metastases' features (solitary or not, unilateral or bilateral, number of liver metastases >3, the diameter of the largest metastasis >5 cm), presence of extrahepatic disease, type of chemotherapy, response to chemotherapy, type of surgery, R0 resection, overall survival, disease-free survival, mortality, morbidity, recurrence rate and modality of recurrence. Patients were classified into two groups based on intervention: preoperative chemotherapy followed by surgery (preoperative group) and upfront surgery followed by chemotherapy (surgery group). The preoperative chemotherapy was divided into oxaliplatin-based, irinotecan-based and chemotherapy plus biological agents. The surgical approach was also divided into three categories: simultaneous primary tumor and liver metastases resection (simultaneous), primary tumor first approach (colon first) and liver first approach (liver first). Patients with a high disease burden were defined as patients with a Clinical Risk Score ≥ 3 [19], patients with more than three metastases or with a maximum diameter > 5 [16,20]. Disputes were resolved by discussion. The inclusion criteria were the following: P(opulation) = adults with synchronous resectable colorectal liver metastases. I(ntervention) = preoperative chemotherapy followed by surgery, and surgery followed by chemotherapy as control.
C(omparison) = all types of comparisons were included. O(utcomes) = overall survival, disease-free survival (primary outcomes), R0 resection, and morbidity (secondary outcomes). A subgroup analysis of patients with high disease burden regarding overall and disease-free survival was also performed.

Statistical Analysis
Categorical variables are described with the use of frequency and continuous variables with medians. Categorical data were analyzed with the use of Chi-square test and continuously using the Mann-Whitney U test.
Summary data methodology meta-analysis of available trials was used for the analyses. The Inverse-Variance (IV) and the Mantel-Haenszel (MH) statistical methods were applied to calculate pooled HRs and ORs. Among studies, heterogeneity was evaluated with Cochran's Q test; in the case of statistically significant heterogeneity (Q test p < 0.1), the Random Effects (RE) model was reported; otherwise, the Fixed Effects (FE) model was adopted to estimate the pooled ratios. I2-statistic was also calculated to assess overall heterogeneity. Some 95% confidence intervals (CIs) were used for the analysis. Statistical significance was set at the two-sided 0.05 level. Rev Man software V5.4 was used to complete the pooled data analysis.
Meta-regression was performed in IBM SPSS V29 to control for confounding variables and identify the independent predictors of disease-free survival and overall survival. Funnel plot and Egger's test [23] were used to assess publication bias. Egger's test was conducted in IBM SPSS V29. In the studies where HR and 95% CI were not directly provided from the published data, we estimated them according to the methods indicated by Parmar et al. [24] and Tierney et al. [25]. Where necessary, the published Kaplan-Meier survival curves were also utilized to reconstruct the data needed for calculating the HR and OR along with their associated 95% CI. For this reason, digitizing software (Get Data Graph Digitizer) was employed to extract the data from the Kaplan-Meier survival curves with the highest precision possible.

Study and Patients' Characteristics
A total of 67 articles were identified through a database search. The full text of 64 articles was retrieved and examined in more detail, while the full text of the remaining three articles was not obtainable. The authors of those three articles were contacted, but unfortunately, no one responded to our query. As a result, these articles were ruled out. Fifty-seven articles were also excluded as they contained no extractable data (53 articles), no comparative group (two articles) or no relevant comparator (two articles). Seven studies were included in the qualitative synthesis. One study was excluded as both groups received preop chemo; six studies matched the selection criteria and were suitable for meta-analysis. Figure 1 illustrates the selection process.
The patients' characteristics of the included studies are summarized in Table 2. Of the 1036 patients with synchronous resectable colorectal liver metastases 59.5% were male, and the median age was 59.1 years. A total of 554 were allocated to the preoperative group, and 482 were allocated to the surgery group. Patients in the preoperative group (57% male, median age 57.9 years) received preoperative chemotherapy. They then underwent liver resection, while patients in the surgery group (62.2% male, median age 60.6 years) underwent upfront liver resection and received postoperative chemotherapy. The primary tumor was usually colon cancer (74.5% vs. 63.9%) and was more often categorized as T3/4 (76.4% vs. 77.8%) in both groups. Metastatic disease was found within the regional lymph nodes in 69.7% of preoperative and 63.1% of patients in the surgery group. Simultaneous resection of the primary lesion and liver metastases was performed in 26.7% of patients in the preoperative group and in 54.6% in the surgery group. Major hepatectomy was more common in the preoperative group than in the surgery group (43.1% vs. 28.8%) p < 0.001. Furthermore, the percentage of patients with more than three liver metastases was higher in the preoperative group compared to the surgery group (12.6% vs. 5.4%) p = 0.002.

Disease-Free Survival
Two RSs reported the incidence of disease-free survival (DFS) in the preoperative and surgery group [17,19], while three RSs reported relapse-free survival (RFS) in the preoperative and surgery group [16,18,20]. Since tumor recurrences may be estimated with DFS or RFS by the investigator's choice, DFS data were analyzed along with RFS data in our study.
Combined DFS and RFS analysis showed that PREC did not significantly affect recurrence (Random Effects pooled HR: 0.98; 95%CI: 0.72-1.34; p = 0.920) (Figure 4). Combined DFS/RFS analysis of patients with high disease burden demonstrated that in these patients, there is a 12% lower risk of recurrence in favor of preoperative chemotherapy; however, this was not statistically significant.

Disease-Free Survival
Two RSs reported the incidence of disease-free survival (DFS) in the preoperative and surgery group [17,19], while three RSs reported relapse-free survival (RFS) in the preoperative and surgery group [16,18,20]. Since tumor recurrences may be estimated with DFS or RFS by the investigator's choice, DFS data were analyzed along with RFS data in our study.
Combined DFS and RFS analysis showed that PREC did not significantly affect recurrence (Random Effects pooled HR: 0.98; 95%CI: 0.72-1.34; p = 0.920) (Figure 4). Combined DFS/RFS analysis of patients with high disease burden demonstrated that in these patients, there is a 12% lower risk of recurrence in favor of preoperative chemotherapy; however, this was not statistically significant.

R0 Resection
R0 resection was assessed by 3 RSs [16,19,20]. Combined analysis showed that patients in the preoperative group had a 29% higher probability of positive hepatectomy margins; however, this was not statistically significant (Fixed Effects, pooled-OR: 1.29; 95%CI: 0.66-2.55; p = 0.46), meaning that the rate of R0 resections between the two groups did not differ significantly ( Figure 6).

Morbidity
Three RSs reported the morbidity rate in the preoperative and surgery groups [18,20]. Combined analysis showed a statistically significant 77% higher probability of postoperative morbidity in patients who received PREC (Fixed Effects, pooled-OR: 1.77; 95%CI:

R0 Resection
R0 resection was assessed by 3 RSs [16,19,20]. Combined analysis showed that patients in the preoperative group had a 29% higher probability of positive hepatectomy margins; however, this was not statistically significant (Fixed Effects, pooled-OR: 1.29; 95%CI: 0.66-2.55; p = 0.46), meaning that the rate of R0 resections between the two groups did not differ significantly ( Figure 6).

R0 Resection
R0 resection was assessed by 3 RSs [16,19,20]. Combined analysis showed that patients in the preoperative group had a 29% higher probability of positive hepatectomy margins; however, this was not statistically significant (Fixed Effects, pooled-OR: 1.29; 95%CI: 0.66-2.55; p = 0.46), meaning that the rate of R0 resections between the two groups did not differ significantly (Figure 6).

R0 Resection
R0 resection was assessed by 3 RSs [16,19,20]. Combined analysis showed that patients in the preoperative group had a 29% higher probability of positive hepatectomy margins; however, this was not statistically significant (Fixed Effects, pooled-OR: 1.29; 95%CI: 0.66-2.55; p = 0.46), meaning that the rate of R0 resections between the two groups did not differ significantly ( Figure 6).

Recurrence Rate
Three RSs [16,18,19] and 1 RCT [21] reported a recurrence rate of 45.2-64.3% in the preoperative group and 47.9-68.8% in the surgery group. Two studies evaluated the modality of recurrence. Intrahepatic recurrence ranged between 42.4 and 66.7% in the preoperative group and between 45.7 and 77.8% in the surgery group, while extrahepatic recurrence varied between 11.1 and 21.2% in the preoperative and between 17.1 and 22.2% in the surgery group. Finally, concurrent intrahepatic and extrahepatic recurrence occurred in 22.2-36.4% in the preoperative group and 0-37.2% in the surgery group [18,19].

Meta-Regression
Finally, meta-regression analyses were performed with a random-effects model using restricted maximum likelihood estimation (RMLE). Results of meta-regression analysis suggested that none of independent variables (age, N Stage and T Stage) were statistically significant predictors of the relationship between clinicopathological factors and Overall Survival (age: HR = 0.79, p = 0.789; N Stage: HR = 2.09, p = 0.950; T Stage: HR = 1.46 p = 0.951).

Discussion
Our meta-analysis could not show any statistically significant difference of PREC vs surgery as far as the outcomes are concerned. We could see a trend in DFS with 12% lower risk of recurrence in favor of preoperative chemotherapy in the group with high-burden disease; however, this was not statistically significant. Interestingly enough, we could see a 29% higher probability of positive hepatectomy margins in the preoperative chemotherapy group; however, this was not statistically significant either. Interestingly, the higher R1 numbers did not affect the overall outcomes of this group. A possible explanation is that adjuvant chemotherapy compensates for the R1 margin and that R1 resection itself is not due to bad surgical technique but rather a potent indicator of aggressive tumor biology [26].
As we can see in Table 2, patients in the PREC group had higher tumor burden as reflected by the higher percentage of patients with more than three liver metastases, the

Recurrence Rate
Three RSs [16,18,19] and 1 RCT [21] reported a recurrence rate of 45.2-64.3% in the preoperative group and 47.9-68.8% in the surgery group. Two studies evaluated the modality of recurrence. Intrahepatic recurrence ranged between 42.4 and 66.7% in the preoperative group and between 45.7 and 77.8% in the surgery group, while extrahepatic recurrence varied between 11.1 and 21.2% in the preoperative and between 17.1 and 22.2% in the surgery group. Finally, concurrent intrahepatic and extrahepatic recurrence occurred in 22.2-36.4% in the preoperative group and 0-37.2% in the surgery group [18,19].

Meta-Regression
Finally, meta-regression analyses were performed with a random-effects model using restricted maximum likelihood estimation (RMLE). Results of meta-regression analysis suggested that none of independent variables (age, N Stage and T Stage) were statistically significant predictors of the relationship between clinicopathological factors and Overall Survival (age: HR = 0.79, p = 0.789; N Stage: HR = 2.09, p = 0.950; T Stage: HR = 1.46 p = 0.951).

Discussion
Our meta-analysis could not show any statistically significant difference of PREC vs surgery as far as the outcomes are concerned. We could see a trend in DFS with 12% lower risk of recurrence in favor of preoperative chemotherapy in the group with high-burden disease; however, this was not statistically significant. Interestingly enough, we could see a 29% higher probability of positive hepatectomy margins in the preoperative chemotherapy group; however, this was not statistically significant either. Interestingly, the higher R1 numbers did not affect the overall outcomes of this group. A possible explanation is that adjuvant chemotherapy compensates for the R1 margin and that R1 resection itself is not due to bad surgical technique but rather a potent indicator of aggressive tumor biology [26].
As we can see in Table 2, patients in the PREC group had higher tumor burden as reflected by the higher percentage of patients with more than three liver metastases, the higher percentage of major hepatectomies and the lower percentage of simultaneous resections of the primary tumor and liver metastases. As we have similar outcomes in both groups, we could suggest that preoperative chemotherapy can potentially be of benefit.
A notable benefit, but still not statistically significant, could be seen in patients with more than three liver metastases, having a 12% lower risk of recurrence. Despite the higher postoperative morbidity in PREC group, the lower recurrence risk cannot be overlooked, so we can suggest PREC in these patients.
This finding can be supported by the European Organization for Research and Treatment of Cancer (EORTC) study 40983 which has shown that neoadjuvant chemotherapy (in initially resectable metastases) could reduce the risk of relapse by one-quarter and allows the testing of the chemosensitivity of cancer to help to determine the appropriateness of further treatments and to observe progressive disease, which contraindicates immediate surgery [27].
Furthermore, one recent retrospective clinical study with 102 patients from Japan has shown that in patients with resectable colorectal liver metastases, the patients with high tumor burden score (TBS) had a survival benefit from preoperative chemotherapy, while the patients with low TBS score benefited from adjuvant chemotherapy. In multivariate analysis, preoperative chemotherapy was an independent prognostic factor for favorable overall survival only in the TBS-high group [9].
The TBS reported recently by Sasaki et al. is a newly developed model that translates the size and the number of liver metastases into one variable using the Pythagorean theorem, and it seems to have better prognostic discriminatory power than traditional tumor morphologic categorization [28].
Another recent study also coming from Japan agrees with the results of our metaanalysis. A retrospective analysis of a multi-institutional cohort of 222 patients showed that the surgical failure-free survival in the sub-group of 53 patients with synchronous liver metastases and high tumor burden (≥5 lesions and/or maximum tumor diameter > 5 cm) was significantly better in the preoperative chemotherapy group compared to the upfront surgery group [29]. A multicenter retrospective trial showed that patients with high clinical risk score (3)(4)(5) benefited from neo-adjuvant chemotherapy [30]. A prospective randomized multicenter clinical trial investigating the role of neo-adjuvant chemotherapy followed by surgery vs. surgery alone in high-risk patients with resectable liver metastases is underway, but the results are not yet available [31].
Unfortunately, our question has not been clearly answered by our meta-analysis. We could only find low quality studies, leading to low evidence. We had a few studies with high heterogeneity in their design which reduced quality.

Conclusions
In conclusion, based on current evidence, we could suggest PREC in patients with high disease burden, but we need to take into consideration the higher morbidity risk. Considering the low to moderate level of evidence our findings urge the need for high-quality, prospective studies investigating the role of PREC in initially resectable liver metastases.

Institutional Review Board Statement:
The study was conducted in accordance with the Declaration of Helsinki. Ethical review and approval were waived for this study due to the fact that this study was a systematic review and meta-analysis.

Conflicts of Interest:
The authors declare no conflict of interest.